Chapter 58 - Structures of Serine/Threonine and Tyrosine Kinases

Abstract

This chapter highlights the structural features of canonical eukaryotic protein kinases and describes a few of the many molecular mechanisms by which their catalytic activity is regulated. Canonical protein kinases are two-domain (bi-lobed) enzymes. The N-terminal lobe (N lobe) comprises a five-stranded anti-parallel β-sheet and an α-helix, and the larger C-terminal lobe (C lobe) comprises seven α-helices and four short β-strands. The polypeptide segment between β5 and α-D connects the N lobe to the C lobe, although a loop N-terminal to this segment, between αC and β4, is anchored in the C lobe, resulting in three pivot points in the rotation of the N lobe relative to the C lobe. ATP binds in the cleft between the two lobes, coordinated primarily by residues in the N lobe. The loop between β1 and β2 contains the nucleotide binding loop, also known as the glycine-rich loop or P (phosphate) loop, and β3 contains a conserved lysine residue, which coordinates the α- and β-phosphate groups of ATP. Receptors, protein serine/threonine kinases (PSK) and protein tyrosine kinases (PTK), are activated by ligand binding to the extracellular region of the receptors, which results in receptor oligomerization and activation through trans-phosphorylation. In the absence of bound ligand, the protein kinase domains in these receptors are maintained in a non-optimized or low-activity state through autoinhibitory interactions that usually involve the activation loop and often the juxtamembrane region (between the transmembrane helix and the kinase domain).